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Possible Involvement of the Autonomic Nervous System in Cervical

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Possible Involvement of the Autonomic Nervous System in Cervical Matsui et al. BMC Musculoskeletal Disorders (2021) 22:419 https://doi.org/10.1186/s12891-021-04293-7 RESEARCH ARTICLE Open Access Possible involvement of the autonomic nervous system in cervical muscles of patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) Takayoshi Matsui1,2, Kazuhiro Hara2, Makoto Iwata1, Shuntaro Hojo1, Nobuyuki Shitara1, Yuzo Endo1, Hideoki Fukuoka1, Masaki Matsui2 and Hiroshi Kawaguchi1* Abstract Background: Patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) sometimes present with stiffness of the cervical muscles. To investigate the pathophysiology of ME/CFS, this observational study compared patients with versus without recovery from ME/CFS through local modulation of the cervical muscles. Methods: Over a period of 11 years, a total of 1226 inpatients with ME/CFS who did not respond to outpatient care were enrolled in this study. All patients received daily cervical muscle physical therapy during hospitalization. Self-rated records documenting the presence or absence of ME/CFS, as well as the representative eight symptoms that frequently accompany it at admission and discharge, were compared. Pupil diameter was also measured to examine autonomic nervous system function involvement. Results: The recovery rate of ME/CFS after local therapy was 55.5%, and did not differ significantlybysex,agestrata,and hospitalization period. The recovery rates of the eight symptoms were variable (36.6–86.9%); however, those of ME/CFS in the symptom subpopulations were similar (52.3–55.8%). The recovery rates of all symptoms showed strong associations with that of ME/CFS (p < 0.001). The pupil diameter was more constricted in the ME/CFS-recovered patients than in the ME/CFS- unrecovered patients in the total population and the subpopulations stratified by sex, age, and hospitalization period. Conclusions: There was a strong association between the recovery of ME/CFS and other related whole-body symptoms. The recovery of ME/CFS may be partly linked to amelioration of the autonomic nervous system in the cervical muscles. Trial registration: UMIN000036634. Registered 1 May 2019 - Retrospectively registered. Keywords: Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS), Autonomic nervous system, Cervical muscle * Correspondence: [email protected] 1Orthopaedics and Spine Department, Tokyo Neurological Center, Toranomon 4-1-17, Minato-ku, Tokyo 105-0001, Japan Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Matsui et al. BMC Musculoskeletal Disorders (2021) 22:419 Page 2 of 9 Background and low back pain [23, 24]. In contrast to the sympa- Myalgic encephalomyelitis / chronic fatigue syndrome thetic nervous system’s excitatory role under stressful (ME/CFS) is a serious, chronic, and complex disease that situations, the parasympathetic nervous system oversees occasionally affects the lives of patients due to debilitat- resting, recovery from stress, and maintenance of ing fatigue [1–4]. It is frequently accompanied by various homeostasis. Several nuclei of the hypothalamus gener- symptoms, such as headache, cervical stiffness, vertigo, ate coordinated patterns of responses of the two systems cardiovascular and gastrointestinal disorders, fever of to internal or social stressors [25]. The pupil light reflex unknown etiology, and psychological disorders. The high is known to be a representative indicator which can be prevalence and low employment rates of patients with used to evaluate autonomic nervous system function. In ME/CFS impose an enormous burden on society. The this reflex action, the constrictor muscle of the pupil de- Institute of Medicine of the National Academy of Sci- creases the diameter of the pupil under control of the ences reported that ME/CFS affects an estimated 2.5 ciliary ganglion, which is activated and innervated by a million people in the United States and generates direct preganglionic autonomic nerve fiber [26–28]. In a recent and indirect expenses of approximately $17–$24 billion study, the preliminary pupil light reflex test performed annually [5]. in a subpopulation, suggested possible autonomic ner- Since ME/CFS is a heterogeneous condition with a vous system dysfunction in the cervical muscles of pa- complex and multifactorial etiology, reaching a conclu- tients with whole-body symptoms [22]. sive diagnosis using the current methods is difficult. Al- To investigate the pathophysiology of ME/CFS, we though several studies have suggested the involvement performed the two cervical muscle physical therapies of abnormal widespread metabolites [6–8], infection and [18–20] in 1226 patients with ME/CFS and examined neurological disorders [9], calcium ion channels [10], or the relationships between ME/CFS recovery and the rep- anaerobic thresholds [11, 12]; the pathogenic mechanism resentative eight whole-body symptoms that frequently of ME/CFS remains unclear. As such, patients are diag- accompany it. Furthermore, to evaluate the possible in- nosed through the exclusion of other conditions that volvement of the autonomic nervous system as an could be responsible for the subjective symptoms with underlying causative mechanism, we also compared the abnormalities across many domains [13, 14]. Thus, treat- changes of the pupil diameters between patients who ment remains symptom-based, multidimensional, and showed ME/CFS recovery versus those who did not tailored to the needs of the individual patient [15, 16]. show ME/CFS recovery. In our clinical experience, we have observed a poten- tial trend of indefinite whole-body symptoms including Methods ME/CFS occasionally coinciding with stiffness of the cer- Study design vical muscles, and have therefore proposed a new med- This study is an observational study which compared pa- ical concept called “cervical neuro-muscular syndrome” tients with versus without recovery from ME/CFS. [17]. For the treatment of the indefinite symptoms, we tried local modulation of the cervical muscles. Among Patients the physical therapies, low-frequency electrical stimula- Of the patients who visited our institutions between May tion [18, 19] and far-infrared irradiation [20] are report- 2006 and May 2017, and were diagnosed with ME/CFS ac- edly effective at treating stiffness of the cervical muscles. cording to Fukuda’sdefinition[13], we enrolled 1363 A previous study of patients with whiplash-associated patients who could not be successfully treated as outpa- disorders showed that the combined application of these tients, and were therefore hospitalized. Outpatient care two physical therapies to the cervical muscles amelio- was variable and included pharmacological and behavioral rated not only local symptoms in the neck and shoulder, strategies but did not include the application of physical but also indefinite symptoms in the whole body [21]. therapies to the cervical muscles. Hospitalization was de- Furthermore, a recent study of 1863 patients showed cided by consent between patients and physicians inde- that therapies applied to the cervical muscles signifi- pendently of the severity of ME/CFS. The main reasons cantly improved the indefinite whole-body symptoms in- for hospitalization were persistent symptoms that required cluding headache, cervical pain or stiffness, vertigo or more intensive treatments, as well as the need for detailed dizziness, palpitation, dazzling, nausea or stomachache, examinations of other organs. Recovery from ME/CFS fever of unknown etiology, and depression [22]. was also defined according to Fukuda’s diagnostic criteria We propose autonomic nervous system involvement [13], mainly by amelioration of chronic fatigue and ex- as an underlying causative mechanism. This system, haustion. Discharge was decided by consent between pa- which regulates the unconscious actions of the body via tients and physicians independent of the ME/CFS the sympathetic and parasympathetic nerves, reportedly recovery by the definition above [13], and was determined plays a role in myalgic disorders such as fibromyalgia mainly by considerable improvement of symptoms of ME/ Matsui et al. BMC Musculoskeletal Disorders (2021) 22:419 Page 3 of 9 CFS or related whole-body symptoms. Patients who were diameter was also measured at admission and discharge, hospitalized for 5–120 days were enrolled. using a binocular infrared pupilometer (Iriscoder Dual C10641; Hamamatsu Photonics, Shizuoka, Japan). Each Intervention patient provided
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